Irregularity in the rhythm of the heart may result from several possible underlying causes which may be hormonal, metabolic (electrolyte imbalance) or circulatory (blood loss, faulty heart valve) in nature. In addition, substances such as tobacco, caffeine, or digitalis may also cause cardiac rhythm disturbances.
One type of cardiac rhythm irregularity is fibrillation, a pathological condition of heart muscle which may be present in either the atria or the ventricles. Atrial fibrillation is an atrial arrhythmia characterized by rapid randomized contractions of the atrial myocardium, causing a totally irregular, often rapid ventricular rate. Ventricular fibrillation is an arrhythmia characterized by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of the myocardial fibers without coordinated contraction of the ventricles. These arrhythmias can be eliminated by the use of electric shock or through the use of certain antiarrhythmic agents. However, although fibrillation can be converted to normal sinus rhythm by the use of antifibrillatory agents, prevention of its recurrence requires chronic therapy for long periods of time. Consequently, these antifibrillatory drugs must not only be effective but they should possess minimal adverse side-effects.
The prevention of sudden coronary death has become a major focus of cardiovascular therapy. The primary cause of sudden coronary death is ventricular fibrillation. Unfortunately, none of the currently available antiarrhythmic drugs is considered suitable for long-term prophylactic use in the prevention of sudden coronary death, nor are any of the newer agents currently under investigation known to prevent ventricular fibrillation. The only currently marketed drug having the potential for the suppression of recurrent ventricular tachyarrhythmias and recurrent ventricular fibrillation is bretylium tosylate; however, it is only used in the acute care setting, primarily due to the possible occurrence of unwanted side effects. These side effects consist of an initial sympathomimetic effect characterized by a significant increase in both heart rate and blood pressure, followed by an antiadrenergic effect which is manifested by the patient becoming dizzy if in a position other than supine. In addition, due to its poor oral bioavailability, bretylium tosylate is only administered intravenously. An experimental antifibrillatory drug, bethanidine, is orally active but it too possesses the unwanted side effects of bretylium. Thus, a great need exists for an orally active drug that will prevent life-threatening ventricular dysrhythmias without the serious side effects of tachycardia and hypertension associated with bretylium tosylate and bethanidine.
In accordance with the present invention, disclosed are compounds having effective antiarrhythmic activity with less of the unwanted activity related to the use of these anti-arrhythmic drugs.